An R21 for CEBRA: The blossoming field of functional neuroimaging studies has pointed to a network of neural structures that subserve the cognitive and behavioral processes of drug addiction, including nicotine. This neural network includes the orbitofrontal cortex, anterior cingulate, insular cortices, the amygdala, and the striatum (dorsal and ventral (nucleus accumbens) striatum). However, no work to date has addressed how damage to different components of this neural network in humans may impact the craving, subjective feeling of drug administration, and active seeking of drugs. Nor any study has asked which, if any, of these components is critically necessary for maintaining the addiction to drugs. This proposal will take advantage of our unique University of Iowa Department of Neurology Patient Registry to begin addressing some of these important issues in patients addicted to cigarette smoking. Our goal is to understand how focal lesions in brain areas hypothesized to be critical neural substrates for addiction affect cigarette smoking behavior, cue-induced craving and smoking urge, as well as the acute subjective effects of smoking. The studies we propose here seek to address 3 specific aims: (1) determining the real-life changes in smoking behavior, cigarette craving, and smoking satisfaction after the onset of brain damage; (2) determining in laboratory experiments the effects of focal brain lesions on (a) the emotional reactivity to smoking cues, (b) the subjective feeling of craving and urge to smoke, and (c) the subjective feeling of smoking a cigarette; and (3) establishing a Registry of neurological patients pre-morbidly known to abuse other substances, including alcohol, stimulants, and opiates, so that they will participate in future research on addiction to drugs. The proposal is promising because (1) it provides a novel perspective for looking at the neurobiological basis of addiction, which compliments and validates the ongoing work with functional neuroimaging techniques; (2) it may help us identify specific brain regions, which damage (or dysfunction) can effectively break the cycle of addiction. The proposed studies are feasible because of (1) our access to the patient population and resources necessary for the conduction of this type research; 2) the guidance of our investigations by an established theoretical framework, the somatic marker hypothesis, and by abundance of background evidence from functional neuroimaging studies. Thus, the proposed research is a beginning of a novel approach with potential for developing more effective therapies for breaking the vicious cycle of addiction.